Lipophilic drug substances having low water solubility are a growing class of drugs with increasing applicability in a variety of therapeutic areas for a variety of pathologies. Many compounds approved for pharmaceutical use are lipophilic compounds with limited solubility and bioavailability. Relatively insoluble compounds, i.e., solubility in water of less than 200 μg/ml may show promising pharmaceutical activity, but their development as pharmaceuticals, particularly in oral dosage form, present a significant challenge to the pharmaceutical industry.
Among the main barriers for effective drug delivery are solubility and stability. To be absorbed in the human body, a compound has to be soluble in both water and fats (lipids). However, solubility in water is often associated with poor fat solubility and vice-versa.
Solubility and stability are, therefore, major obstacles hindering the development of therapeutic agents. Aqueous solubility is a necessary but frequently elusive property for formulations of the complex organic structures found in pharmaceuticals. Traditional formulation systems for very insoluble drugs have involved a combination of organic solvents, surfactants and extreme pH conditions. These formulations are often irritating to the patient and may cause adverse reactions. At times, these methods are inadequate for solubilizing enough of a quantity of a drug for a parenteral formulation.
Bioavailability refers to the degree to which a drug becomes available to the target tissue or any alternative in vivo target (i.e., receptors, tumors, etc.) after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water-soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
In order to increase the solubility of poorly soluble drugs, several techniques have been used such as (i) selection of more soluble polymorphs, hydrates or salts; (ii) addition of additives as surfactants to solubilize the drug; and (iii) use of particle size reduction (e.g., micronization) which increases the area of drug in contact with the medium, to accelerate dissolution. These techniques, however, were sometimes inadequate to provide satisfactory solubility.
More sophisticated solubilization approaches have been developed in recent years, based on; (i) a new generation of size reduction technology; (ii) advanced solubilizing agents that “drag” the insoluble drug into solution and increase the miscibility of the drug with aqueous media; and (iii) use of amorphous forms or eutectic mixtures to reduce the thermodynamic barriers to dissolution
With regard to the size reduction, it is known that the rate of dissolution of a particulate drug can increase with increasing surface area, namely, decreasing particle size. It is generally accepted that water insoluble or poorly water-soluble drugs can be made more bioavailable when presented in the form of small particles. The new techniques for size reduction reduce the particle size to a much greater extent than ever previously seen; hence the micronization of the past has been replaced by new technologies that produce nanoparticles, which are up to 1000 times smaller. Above and beyond the dramatic increase in surface area seen with nanoparticles (and the consequent effects on the rate of dissolution), it has been suggested that the use of particles in the nanosize range may even increase the saturation solubility of a drug in an aqueous medium and allow local supersaturation.
Nanoparticles can be generated by many different means, such as size reduction by advanced milling techniques or by precipitation. However, after the formation of the drug nanoparticles, many of these techniques face a common problem: the tendency of very small drug particles to agglomerate together. Many of the inventions in the field focus on preventing this agglomeration, often by coating the nanoparticles
A number of solubilization technologies for water-insoluble drugs exist such as nanosuspensions, nanoparticles, liposomes, cyclodextrins, dendrimers, micro- and nanoencapsulation, and solid dispersion, but each of these technologies has a number of significant disadvantages.
One of the methods employed to increase the surface area of particles and thus enhance the solubility of water-insoluble compounds in drug formulations is to make a solid dispersion of insoluble pharmaceutical substances in high molecular weight water-soluble polymeric matrices, which act as a solubility bridge between the insoluble compound and an aqueous medium (Christian Leuner and Jennifer Dressman, 2000, Improving drug solubility for oral delivery using solid dispersions, European Journal of Pharmaceutics and Biopharmaceutics, 50: 47-60). A solid dispersion always contains at least two components: a matrix and a drug. The matrix can be either amorphous or crystalline, and the drug can be dispersed within the matrix as a molecular dispersion or as nanosized crystals or as amorphous particles. It is currently not clear how the complex interactions between drug-matrix and aqueous solvent improve the solubility of the drug.
Solid dispersions are physico-chemically classified as eutectics, solid solutions, glass solutions, glass suspensions, amorphous precipitate in a glassy or crystalline carrier, complex formation and/or a combination of the different systems. With the proper choice of polymers it is possible to significantly increase the solubility of the drug substance as well. Although there are a few marketed drugs that have been formulated as solid dispersions, the major obstacle has been that they are insufficiently stable, and in order to be able to apply these dispersions widely in the pharmaceutical area significant stability improvements are needed.
Forming a stable mixture of polymer matrix and drug, which maximizes the dissolution properties of the drug when exposed to aqueous medium (GI fluid) and which is preferably as uniform as possible is the aim when preparing solid dispersions.
Solid dispersion dosage forms may be formed by solvent method, by spray drying, by spraying drug solution onto the carrier in a fluidized bed granulator, by melt extrusion, by melt fusion, twin-screw extruder, evaporation, curing, microwaving, milling, ultra sound, spinning by mechanical admixture such as by ball milling and by mechanical admixture at an elevated but non-melting temperature. See, for example, U.S. Pat. No. 4,880,585, U.S. Pat. No. 5,456,923, U.S. Pat. No. 6,254,889, U.S. Pat. No. 6,387,401, U.S. Pat. No. 6,706,283, U.S. Pat. No. 6,599,528, and US 2004/0013697.
The solvent method for the preparation of solid dispersions of poorly-soluble drugs involves the dissolution of the matrix material in a solvent. The drug is either suspended or dissolved in the matrix-solvent mixture and the solvent is then removed to leave a mixture of drug and matrix. Separation methods include precipitation, freeze-drying, vacuum drying or spray drying.
To dissolve the drug and the matrix in a common solvent is a considerable problem. If low drug concentrations and large amounts of solvent are used, the process of removing the solvent becomes expensive and impractical. Surfactants like Tween and solubilizing agents like cyclodextrins have been used, however this can lead to low drug loads and high concentrations of surfactants, which then change the properties of the matrix and which may be poorly-tolerated or even toxic. Suitable solvents may only be found in those regarded by the FDA as toxic, which renders them impractical for pharmaceutical use.
Thus, despite many years of research and development and despite its theoretical promise, solid dispersion approach has proved to be limited in its practical application. Its problems include: (i) lack of a scientific framework and the need to use trial and error—only a specific matrix developed for a specific drug; (ii) problems of scale up with the methods used; and (iii) problems with the physical and chemical stability of the drug-polymer matrix. The problems with matrix selection are due to the mutual incompatibility of the various requirements: low hygroscopicity, fast dissolution, stability and easy to manufacture. So for instance, a polar matrix, which aids dissolution, when combined with a lipophilic drug, is inherently prone to phase separation, a tendency that can be magnified if the polar matrix is also hygroscopic, which reduces stability. On the other hand, a stable matrix requires low molecular mobility (to prevent phase changes of the drug), this usually requires high molecular weight, which makes it difficult to find a common solvent for drug and polymer. However, if the matrix is made from a less polar polymer, in order to more easily find a common solvent, then the dissolution rate is impaired. It would be highly desirable to find the ideal matrix and a simple production process.
U.S. Pat. No. 5,145,684 discloses dispersible particles consisting essentially of a crystalline drug substance having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm and dispersions containing the particles exhibit unexpected bioavailability
WO 2004/069138 discloses a process for preparing a solid dispersion pharmaceutical product containing a pharmaceutical active ingredient and a polymer, wherein the pharmaceutical active ingredient is relatively insoluble and has a lower melting point or glass transition point than the water soluble polymer of choice, comprising first liquefying or softening the active ingredient and then adding the polymer to produce a mixture of the liquefied or softened pharmaceutical active ingredient with the polymer, then allowing said liquefied or softened mixture to become liquefied throughout, then allowing said mixture to form a molecular dispersion of pharmaceutical active ingredient and polymer, and then solidifying said dispersion in order to create a solid dispersion. Preferred polymers are polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC). Also hydrophobic polymers and mixtures of polymers can be used. The pharmaceutical active ingredient is preferably first melted and then mixed with a water-soluble polymer.
U.S. Pat. No. 6,337,092 discloses pharmaceutical compositions comprising electrostatic and steric-stabilized sub-micron and micron-size stable microparticles of water-insoluble or poorly soluble drugs, the particles having phospholipid coated surfaces and being stabilized with a combination of a highly purified charged phospholipid surface modifier and a block copolymer of ethylene oxide and propylene oxide.
US 2002/009494 discloses a composition comprising spray dried solid dispersions comprising a sparingly soluble drug and hydroxypropylmethylcellulose acetate succinate (HPMCAS) that provide increased aqueous solubility and/or bioavailability in a use environment.
US 2004/0052847 discloses a method of manufacturing an active agent oral dosage form, said method comprising the steps of: providing a single phase working solution comprising an active agent, water, a water-soluble polymer and a solvent, said solvent selected from the group consisting of alcohol, acetone, and mixtures thereof; providing core particles formed from a pharmaceutically acceptable material; combining said working solution with said particles to produce active agent-coated particles; drying said active agent-coated particles; and forming said dried particles into an oral dosage form.
Numerous patents/patent applications deal with the preparation of compositions comprising fenofibrate, a lipophilic drug useful for treating hyperlipidemia, particularly to reduce cholesterol and triglyceride levels in patients at risk of cardiovascular disease. Thus, several compositions have been developed or proposed to improve the solubility and bioavailability of fenofibrate and to reduce the food effect of blood levels of the active drug.
U.S. Pat. No. 4,961,890 discloses a process for preparing a controlled release formulation containing fenofibrate in an intermediate layer in the form of crystalline microparticles included within pores of an inert matrix. Sheu M T et al. (Int. J. Pharm. 103:137-146, 1994) reported that a dispersion of fenofibrate in polyvinylpyrrolydone (PVP) still maintains the same crystalline form of the drug itself. Palmieri G F et al. (Pharma Sciences 6:188-194, 1996) reported that a dispersion of crystalline fenofibrate could be prepared in PEG 4000.
U.S. Pat. No. 6,074,670, U.S. Pat. No. 6,277,405, U.S. Pat. No. 6,589,522 and U.S. Pat. No. 6,652,881 (assigned to Laboratoires Fournier) disclose an immediate-release fenofibrate composition comprising an inert hydrosoluble carrier covered with at least one layer containing a fenofibrate active ingredient in a micronized form having a size less than 20 μm, a hydrophilic polymer and a surfactant, and optionally one or several outer phase(s) or layer(s).
U.S. Pat. No. 6,368,622 (assigned to Abbott Laboratories) discloses a process for preparing a solid formulation of a fibrate, particularly fenofibrate, exhibiting more rapid dissolution, comprising forming a mixture of the fibrate with a solid surfactant and granulating the mixture by melting, mixing, and congealing, then optionally forming a finished dosage form. U.S. Pat. No. 6,465,011 (Abbott Laboratories) discloses a composition comprising a fibrate, particularly fenofibrate, dissolved in a hydrophilic, amorphous polymer carrier in which said fibrate is present as a metastable, amorphous phase. WO 00/72829 (Abbott Laboratories) discloses a composition for lipid-regulating drugs including fenofibrate comprising the active drug and excipient in a eutectic mixture.
U.S. Pat. No. 7,037,529 and U.S. Pat. No. 7,041,319 (assigned to Laboratoires Fournier) disclose fenofibrate compositions comprising granulates, wherein the granulates comprise inert carrier particles coated with an admixture comprising at least one hydrophilic polymer, micronized fenofibrate and optionally a surfactant and wherein the composition has a high dissolution rate in solutions of surfactants.
US 2006/0222707, assigned to Teva Pharmaceuticals, discloses a pharmaceutical composition comprising a fibrate drug, particularly fenofibrate, in intimate association with a surfactant mixture comprising PEG 6000 and Poloxamer 407. The composition is prepared by a process comprising: (a) providing melted menthol; (b) mixing melted menthol with the fibrate drug and a surfactant mixture comprising PEG 6000 and Poloxamer 407 to dissolve at least part of the fibrate drug and the surfactant mixture, and removing the menthol via sublimation.
WO 2006/060817 (Abbott Laboratories) discloses an oral pharmaceutical composition comprising fenofibrate and at least one pharmaceutically acceptable polymer and, optionally, at least one pharmaceutically acceptable surfactant. The composition can be in the form of a solid dispersion that forms a suspension upon in contact with an aqueous medium. The suspension comprises crystalline and/or amorphous fenofibrate particles of various particle sizes. The solid dispersions are prepared by a melt-extrusion method.
US 2003/0224058 (now U.S. Pat. No. 7,276,249), US 2004/0058009, US 2004/0087656 and US 2005/0276974, US 2006/0110444, US 2006/0222707 and WO 2004/041250, (assigned to Elan Pharma and Fournier Laboratories) disclose nanoparticulate compositions comprising a fibrate, preferably fenofibrate, and at least one surface stabilizer adsorbed on the surface of the fibrate particles. The fenofibrate particles have an effective average particle size of less than about 2000 nm and are obtained by milling, homogenization or precipitation techniques and then coating by the surface stabilizers to prevent aggregation. The formulations containing fenofibrate as either a nanoparticulate or a molecular dispersion in a solid dosage form eliminate the food effect associated with fenofibrate.
Some more recent publications disclose methods and compositions comprising low-solubility drugs and two polymers.
US 2003/0104063 discloses a pharmaceutical composition comprising: (a) a solid dispersion comprising a low-solubility drug and a matrix (which can be formed by one or more polymers), wherein at least a major portion of said drug in said dispersion is amorphous; and (b) a concentration-enhancing polymer which further improves solubility in the use environment and may not be part of the drug/matrix dispersion, instead it is mixed in with the drug/matrix particles or given separately.
US 2003/0228358 discloses a pharmaceutical composition comprising a solid amorphous dispersion of a low-solubility drug and a concentration-enhancing polymer, administered together with a lipophilic microphase-forming material, which may be present as part of the solid amorphous dispersion or mixed in with the dispersion or even given separately with the dispersion.
US 2007/0141143 discloses a solid composition comprising a plurality of particles, said particles comprising a low-solubility drug and a poloxamer, at least a substantial portion of said drug in said particles being amorphous and being in intimate contact with said poloxamer in said particles, and further optionally comprising a concentration-enhancing polymer.
US 2007/0148232 discloses solid compositions with improved physical stability comprising an amorphous, low-solubility drug, a poloxamer, and a stabilizing polymer, preferably a cellulosic polymer. The compositions are prepared by a solvent-based process and spray-drying and provide good physical stability during storage and concentration enhancement of dissolved drug when administered to an aqueous environment.
Statins are currently among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. Statins are also known to raise HDL cholesterol levels and decrease total triglyceride levels. The main statins currently used in therapeutics are: pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and rosuvastatin.
US 2001/0006662 discloses a composition comprising a lipid-regulating agent, e.g. atorvastatin or pravastatin, dissolved or dispersed in a hydrophilic, amorphous polymer in which said lipid-regulating agent is present as a meta-stable, amorphous phase. WO 03/103640 describes a nanoparticulate composition (effective average particle size less than about 2000 nm) comprising statin such as lovastatin or simvastatin including surface stabilizer or combinations of statin and other cholesterol lowering agents. US 2002/0034546 discloses a pharmaceutical composition which is useful for cholesterol lowering and reduction of the risk of myocardial infarction, which includes a statin, such as pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin or fluvastatin, in combination with aspirin, in a manner to minimize interaction of aspirin with the statin and to minimize side effects of aspirin.
Compositions comprising fenofibrate and a statin have been described. US 2005/0096391 discloses a particulate material comprising fenofibrate and rosuvastatin in a hydrophobic, a hydrophilic or a water-miscible vehicle. US 2006/0068015 and US 2007/0009603 discloses pharmaceutical compositions in particulate form or in solid dosage forms comprising a combination of fenofibrate and atorvastatin, which are manufactured without any need of addition of water or aqueous medium and comprise at least 80% of the active substances fenofibrate and atorvastatin in dissolved form, or, optionally, atorvastatin in micronized form, in order to ensure suitable bioavailability.
Compositions comprising tacrolimus, an immunosuppressive lipophilic drug used mainly after allogenic organ transplant to prevent organ rejection, have been described. US 2006/0159766 is directed to nanoparticulate tacrolimus compositions comprising tacrolimus particles having an effective average particle size of less than about 2000 nm and at least one surface stabilizer. US 2006/0287352 discloses a modified release composition comprising tacrolimus that may be coated with an enteric coating and/or may comprise a solid dispersion or a solid solution of tacrolimus in a hydrophilic or water-miscible vehicle and one or more modifying release agents; and/or may comprise a solid dispersion or a solid solution of tacrolimus in an amphiphilic or hydrophobic vehicle and optionally one or more modifying release agents. U.S. Pat. No. 6,884,433 describes sustained-release formulation comprising a solid dispersion composition, wherein the solid dispersion composition comprises tacrolimus or its hydrate, in a mixture comprising a water-soluble polymer and a water-insoluble polymer, and an excipient.
US 2004/0198645 discloses a solid pharmaceutical composition comprising a poorly water-soluble drug (e.g. cyclosporin A), a polymer which is solid at room temperature, and a surfactant which is solid at room temperature and which has a HLB value of between 8 and 17.
U.S. Pat. No. 7,101,576 discloses a megestrol acetate formulation comprising megestrol particles having an effective average particle size of less than about 2000 nm, and at least one surface stabilizer (e.g., polymer) associated with the surface of the particles.
US 20060062809 describes solid dispersions comprising a poorly soluble bioactive compound (e.g. itraconazole) dispersed and characterized in a polymer matrix which may comprise more than one polymer. US 2005/0191359 of the present applicant discloses a hydrophilic dispersion of nano-sized particles comprising an active compound selected from a macrolide antibiotic, donepezil hydrochloride, an azole compound (e.g. itraconazole) and a taxane; and an amphiphilic polymer which wraps said active compound in a non-crystalline manner to form a nano-sized molecular entity in which no valent bonds are formed.
U.S. Pat. No. 6,221,399 describes a method of making a solid interpolymer complex for use as a controlled release matrix for a controlled release product for oral administration, from a first polymer and one or more second complementary polymers capable of complexing with the first polymer to form the interpolymer complex, wherein one of the first polymer or the second complementary polymer is a synthetic polymer, including the steps of: (i) dissolving the first polymer in a solvent; (ii) dissolving the second complementary polymer in a solvent therefor, the solvent for said second polymer being the same as that used for step (i) or different; (iii) the solvent in at least one of step (i) or (ii) functioning as a complexation inhibitor or adding a complexation inhibitor to the solution of step (i) or the solution of step (ii), so that a complexation inhibitor is present to prevent the interpolymer complex from precipitating from solution prior to step (vi); (iv) mixing together the solutions of steps (i) and (ii); (v) if necessary, adjusting the pH of the mixture of step (iv) to insure the desired complexation when solvent is removed while avoiding precipitation of the complex; and (vi) spraying the resulting solution into a vessel to remove solvent, including any complexation inhibitor added thereto, to enable the polymers to complex and thereby produce solid particles of said complex.
US 2006/0062809 describes solid dispersions comprising a poorly soluble bioactive compound dispersed in a polymer matrix comprising more than one polymer, characterized in that a first polymer allows a homogenous or molecular dispersion of the bioactive compound in the polymer matrix, while a second polymer has a dissolution profile associated with the creation of a micro-environment enhancing the dissolution of the bioactive compound in an aqueous environment.
US 2007/0026062 describes a solid dosage form comprising a solid dispersion or solid solution of a fibrate selected from gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and active metabolites and analogues thereof including any relevant fibric acid such as fenofibric acid in a vehicle, which is hydrophobic, hydrophilic or water-miscible, wherein the therapeutic effect of the solid dosage form in a patient is essentially independent of whether the solid dosage form is administered to the patient in fed or fasted state.
Although numerous patents/patent applications propose different methods for the preparation of formulations of lipophilic agents, there is still a need for such formulations exhibiting immediate release and improved bioavailability and for methods for their preparation that are more efficient and less complex than the available methods.